Background: NKG2A is an inhibitory receptor of both T cells and natural killer (NK) cells. Persistent activation promotes T cells and NK cells to express NKG2A and results in the progression of chronic infection and cancer. However, the characteristics and subsets of NKG2A + lymphocytes in human lung cancer are still unclear.Methods: Here, we used the Tumor Immune Estimation Resource database and immune profiling of paired biospecimens to uncover the correlation between NKG2A expression and immune infiltration levels in human cancer as well as the characteristics of NKG2A + lymphocytes in human lung cancer.Results: We found that KLRC1 expression was especially correlated with CD8 + T-cell infiltration levels in 34 types of human cancer through the Tumor Immune Estimation Resource database. Moreover, NKG2A + CD8 + T cells were the predominant subset of NKG2A + lymphocytes in human lung cancer. In contrast, the NKG2A + NK cells were decreased in tumors compared with the paired normal lung tissue. Tumor-infiltrating NKG2A + CD8 + T cells expressed tissue-resident memory T cell (T RM cell) and exhausted T-cell markers. Cytokines and cytotoxic molecules secreted by tumor-infiltrating NKG2A + CD8 + T cells were significantly lower than those secreted by NKG2A − CD8 + T cells in vitro. When stimulated with T-cell receptor activator, tumor-infiltrating NKG2A + CD8 + T cells could secrete large amounts of granzyme B.Conclusions: Our findings demonstrate that tumor-infiltrating NKG2A + CD8 + T cells form the predominant subset of NKG2A + cells in human lung cancer and suggest that targeting NKG2A + CD8 + T cells is a promising approach for future anti-lung cancer immunotherapy.

Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25 + cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1 + medullary TEC-like cells that are the characteristic feature of type 3 TETs don’t seem to support T-cell development, however, they may induce a tissue-resident CD8 + T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.

Inducing a full antitumor immune response in the tumor microenvironment (TME) is essential for successful cancer immunotherapy. Here, we report that an oncolytic adenovirus carrying mIL-15 (Ad-IL15) can effectively induce antitumor immune response and inhibit tumor growth in a mouse model of cancer. We found that Ad-IL15 facilitated the activation and infiltration of immune cells, including dendritic cells (DCs), T cells and natural killer (NK) cells, in the TME. Unexpectedly, we observed that Ad-IL15 also induced vascular normalization and tertiary lymphoid structure formation in the TME. Moreover, we demonstrated these Ad-IL15-induced changes in the TME were depended on the Ad-IL15-induced activation of the STING-TBK1-IRF3 pathway in DCs. Taken together, our findings suggest that Ad-IL15 is a candidate for cancer immunotherapy that promotes immune cell activation and infiltration, tumor vascular normalization and tertiary lymphoid structure formation in the TME.

Background CD38 has been observed expressing in activated T cells, while the features and functions of CD38+ T cells in human NSCLC are still unclear. Methods Here we uncovered the correlation between CD38 expression and survival and immune infiltration levels in tumor of NSCLC. Then, we collected samples from 51 NSCLC patients to study the biological feature and response to anti-PD-1 of tumor-infiltrating CD38+ CD8+ T cells in vitro. Results We found CD38 expression correlated with the survival and immune infiltration levels of NSCLC. It is interesting that CD38+ CD8+ T cells enriched in the tumors expressed higher level of cytotoxic molecule, cytokines and PD-1 than CD38− CD8+ T cells. Moreover, PD-1+ subset in tumor-infiltrating CD38+ CD8+ T cells expressed higher level of activated markers than PD-1+ CD38− CD8+ T cells. Next, we found tumor-infiltrating CD38+ CD8+ T cells expressed higher level of CD103, IFN-γ, TNF-α and perforin than CD38− CD8+ T cells when were reactivated in vitro. Finally, we observed that CD38+ CD8+ T cells isolated from tumors could be reinvigorated by anti-PD-1 in vitro. Conclusions Our findings demonstrate that CD38 expression defines a subset of CD8+ T cells enriched in tumors of NSCLC which have paradoxical phenotypes and response to anti-PD-1. Our results suggest a pre-priming of these cells is may exist in tumor and consequentially facilitate it acquiring both anti-tumor potency and exhausted phenotype which can be reinvigorated by PD-1 blockade.

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